Engineered Immune Cells with B2M Deletion for Allogeneic Therapy
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Solution Overview
Problem
Allogeneic immune cell transplants in adoptive cell therapy face complications such as graft versus host disease and reduced efficacy due to autocrine signaling and immune cell activation, which can lead to unintended inactivation or excessive activation of immune cells, reducing therapy effectiveness and increasing the risk of side effects.
Innovation Solution
Engineered immune cells with reduced or eliminated beta-2-microglobulin (B2M) expression, using interfering RNA like short hairpin RNA (shRNA) to target B2M mRNA, are developed to minimize autocrine signaling and enhance specificity and safety by incorporating an inhibitory receptor with a ligand binding domain specific to a class I major histocompatibility complex molecule, thereby reducing unwanted activation and improving targeting of cancer cells.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Measurement precision
If immune cells express inhibitory receptors to increase specificity for target cells, then specificity is improved, but autocrine signaling causes unintended inactivation or activation of the immune cell
Solution Approach 1:
The patent removes the problematic component (endogenous MHC class I molecules) from the immune cell system using CRISPR-Cas9 gene editing to delete the B2M gene, which encodes beta-2 microglobulin, a necessary component for MHC class I assembly. This extraction eliminates the source of autocrine signaling while preserving the desired inhibitory receptor function for targeting cancer cells.
Solution Approach 2:
The patent introduces an intermediary substance (interfering RNA or CRISPR-Cas9 system) to mediate the removal of endogenous MHC class I molecules. This intermediary mechanism allows precise control over gene deletion while maintaining the integrity of the engineered inhibitory receptors and other cellular functions.
2Productivity
If allogeneic immune cells are transplanted to treat cancer, then therapy efficacy is improved, but graft versus host disease and host versus graft disease occur
Solution Approach 1:
The patent applies local quality modification by selectively deleting the B2M gene in the allogeneic immune cells, creating a localized genetic modification that reduces MHC class I expression specifically in the transplanted cells. This localized change reduces recognition by the recipient's immune system while preserving the cells' cancer-fighting capability through the engineered inhibitory receptors.
Solution Approach 2:
The patent changes the genetic parameter (B2M gene expression) of the allogeneic immune cells to reduce MHC class I molecule surface expression. This parameter modification alters the immunological profile of the transplanted cells, reducing their visibility to the recipient's immune system and thereby reducing host versus graft disease while maintaining therapy efficacy.
3Reliability
If endogenous MHC class I molecules are present in immune cells, then normal immune function is maintained, but binding in cis or autocrine signaling reduces therapy effectiveness
Solution Approach 1:
The patent extracts and removes the problematic endogenous MHC class I molecules from the immune cell surface through CRISPR-Cas9-mediated deletion of the B2M gene. This extraction eliminates the source of autocrine signaling that was interfering with therapy effectiveness, while the engineered inhibitory receptors continue to provide targeted cancer cell recognition and destruction.
Applied Scientific Principles
This section explains which scientific principles are used to turn an abstract innovation direction into a practical engineering solution.
Function Achieved in This Case
The approach reduces autocrine signaling in immune cells, enhancing their specificity and safety, thereby improving the efficacy and reducing complications of allogeneic immune cell transplants by preventing unintended activation and improving targeting of cancer cells, leading to more effective and safer adoptive cell therapies.
Implementation Method 1
expression of a B2M-targeting interfering RNA by the immune cell
Implementation Method 2
capable of inducing RNAi-mediated degradation of the B2M mRNA
Data Source
AI summary
The disclosure relates to immune cells for use in adoptive cell therapy useful for treating a disease or disorder, for example, cancer. The disclosure provides immune cells with reduced or eliminated B2M expression, that express an inhibitory receptor, methods of making same, shRNAs targeting B2M mRNA, and polynucleotides and vectors encoding same.